Saturday, October 31, 2015

The pathological fear of being buried alive is called taphophobia.1 This seems like a perfectly rational fear to me, especially if one is claustrophobic and enjoys horror movies and Edgar Allan Poe shortstories. Within a modern medical context, however, it simply not possible that a person will be buried while still alive.

But this wasn't always the case. In the 19th century, true stories of premature burial were common, appearing in newspapers and medical journals of the day. Tebb and Vollum (1896) published a 400 page tome (Premature burial and how it may be prevented: with special reference to trance, catalepsy, and other forms of suspended animation) that was full of such examples:

The British Medical Journal, December 8, 1877,
p. 819, inserts the following : —

"BURIED ALIVE.

"A correspondent at Naples states that the Appeal Court has had before it a case not likely to inspire confidence in the minds of those who look forward with horror to the possibility of being buried alive. It appeared from the evidence that some time ago a woman was interred with all the usual formalities, it being believed that she was dead, while she was only in a trance. Some days afterwards, the grave in which she had been placed being opened for the reception of another body, it was found that the clothes which covered the unfortunate woman were torn to pieces, and that she had even broken her limbs in attempting to extricate herself from the living tomb. The Court, after hearing the case, sentenced the doctor who had signed the certificate of decease, and the mayor who had authorised the interment, each to three months' imprisonment for involuntary manslaughter."

To avoid this fate worse than death, contraptions known as “safety coffins” were popular, with air tubes, bells, flags, and/or burning lamps (Dossey, 2007). Some taphophobes went to great lengths to outline specific instructions for handling their corpse, to prevent such an ante-mortem horror from happening to them. Some might even say these directives were a form of “overkill”...

From the Lancet, August 20, 1864, p. 219.

"PREMATURE INTERMENT.

"Amongst the papers left by the great Meyerbeer, were some which showed that he had a profound dread of premature interment. He directed, it is stated, that his body should be left for ten days undisturbed, with the face uncovered, and watched night and day. Bells were to be fastened to his feet. And at the end of the second day veins were to be opened in the arm and leg. This is the gossip of the capital in which he died. The first impression is that such a fear is morbid. No doubt fewer precautions would suffice, but now and again cases occur which seem to warrant such a feeling, and to show that want of caution may lead to premature interment in cases unknown. An instance is mentioned by the Ost. Deutsche Post of Vienna. A few days since, runs the story, in the establishment of the Brothers of Charity in that capital, the bell of the dead-room was heard to ring violently, and on one of the attendants proceeding to the place to ascertain the cause, he was surprised at seeing one of the supposed dead men pulling the bell-rope. He was removed immediately to another room, and hopes are entertained of his recovery."

Here's a particularly gruesome one:

From the Daily Telegraph, January 18, 1889.

"A gendarme was buried alive the other day in a village near Grenoble. The man had become intoxicated on potato brandy, and fell into a profound sleep. After twenty hours passed in slumber, his friends considered him to be dead, particularly as his body assumed the usual rigidity of a corpse. When the sexton, however, was lowering the remains of the ill-fated gendarme into the grave, he heard moans and knocks proceeding from the interior of the 'four-boards.' He immediately bored holes in the sides of the coffin, to let in air, and then knocked off the lid. The gendarme had, however, ceased to live, having horribly mutilated his head in his frantic but futile efforts to burst his coffin open."

Doesn't that sound like fun? Wouldn't you like to experience this yourself? Now you can!

The game uses a real life coffin, an Oculus Rift, a PC and some microphones. One player gets in the coffin with the Rift on, together with a headset + microphone. The other player plays on a PC again with mic + headset, this player will play a first person game where they must work with the buried player to uncover where the coffin is and rescue the trapped player before their oxygen runs out. This is all powered by the Unity engine.

This work is intended to explore “uncomfortable experiences and interactions” as part of academic research in the Human Computer Interaction field (HCI) from an MSc by Research in Computer Science student, James Brown. The player inside the coffin will experience various emotions as they are put in and then try to get out of the confined space. Claustrophobia as well as the fear of being buried alive “taphophobia” may well affect players of the game and they must cope with these emotions as they play.

Tebb W, Vollum EP. (1896). Premature burial and how it may be prevented: with special reference to trance, catalepsy, and other forms of suspended animation. SWAN SONNENSCHEIN & CO., LIM.: London. {archive.org}

Horror movies where people turn into snakes are relatively common (30 by one count), but clinical reports of delusional transmogrification into snakes are quite rare. This is in contrast to clinical lycanthropy, the delusion of turning into a wolf.

What follows are two frightening tales of unresolved mental illness, minimal followup, and oversharing (plus mistaking an April Fool's joke for a real finding).

THERE ARE NO ACTUAL PICTURES OF SNAKESin this post [an important note for snake phobics].

A 24 year young girl presented to us with complaints that she had died 15 days before and that in her stead she had been turned into a live snake. At times she would try to bite others claiming that she was a snake. ... We showed her photos of snakes and when she was made to face the large mirror she failed to identify herself as her real human self and described herself as snake. She described having snake skin covering her and that her entire body was that of snake except for her spirit inside. ... She was distressed that others did not understand or share her conviction. She felt hopeless that nothing could make her turn into real self. She made suicidal gestures and attempted to hang herself twice on the ward...

The initial diagnosis was severe depressive disorder with psychotic features. A series of drug trials was unsuccessful (Prozac and four different antipsychotics), and a course of 10 ECT sessions had no lasting effect on her delusions. The authors couldn't decide whether the patient should be formally diagnosed with schizophrenia or a more general psychotic illness. Her most recent treatment regime (escitalopram plus quetiapine) was also a failure because the snake delusion persisted.

“Our next plan is to employ supportive psychotherapy in combination with pharmacotherapy,” said the authors (but we never find out what happened to her). Not a positive outcome...

Ophidiantrophy with paranoid schizophrenia, cannabis use, bestiality, and history of epilepsy

The second case is even more bizarre, with a laundry list of delusions and syndromes (Mondal, 2014):

A 23 year old, married, Hindu male, with past history of ... seizures..., personal history of non pathological consumption of bhang and alcohol for the last nine years and one incident of illicit sexual intercourse with a buffalo at the age of 18 years presented ... with the chief complains of muttering, fearfulness, wandering tendency ... and hearing of voices inaudible to others for the last one month. ... he sat cross legged with hands folded in a typical posture resembling the hood of a snake. ... The patient said that he inhaled the breath of a snake passing by him following which he changed into a snake. Though he had a human figure, he could feel himself poisonous inside and to have grown a fang on the lower set of his teeth. He also had the urge to bite others but somehow controlled the desire. He said that he was not comfortable with humans then but would be happy on seeing a snake, identifying it belonging to his species. ... He says that he was converted back to a human being by the help of a parrot, which took away his snake fangs by inhaling his breath and by a cat who ate up his snake flesh once when he was lying on the ground. ... the patient also had thought alienation phenomena in the form of thought blocking, thought withdrawal and thought broadcasting, delusion of persecution, delusion of reference, delusion of infidelity [Othello syndrome], the Fregoli delusion, bizarre delusion, nihilistic delusion [Cotard's syndrome], somatic passivity, somatic hallucinations, made act [?], third person auditory hallucinations, derealization and depersonalisation. He was diagnosed as a case of paranoid schizophrenia as per ICD 10.

Wow.

He was was given the antipsychotic haloperidol while being treated as an inpatient for 10 days. Some of his symptoms improved but others did not. “Long term follow up is not available.”

The discussion of this case is a bit... terrifying:

Lycanthropy encompasses two aspects, the first one consisting of primary lupine delusions and associated behavioural deviations termed as lycomania, and the second aspect being a psychosomatic problem called as lycosomatization (Kydd et al., 1991).

Endogenous lycanthropogens responsible for lycomania are lupinone and buldogone which differ by only one carbon atom in their ring structure; their plasma level having a lunar periodicity with peak level during the week of full moon. Lycosomatization likely depends on the simultaneous secretion of suprathreshold levels of both lupinone and the peptide lycanthrokinin, a second mediator, reported to be secreted by the pineal gland, that “initiates and maintains the lycanthropic process” (Davis et al., 1992). Thus, secretion of lupinone without lycanthrokinin results in only lycomania. In our patient these molecular changes were not investigated.

THE MORGUE:
David Blake - Our hapless victim. David is a college student who gets recruited by Dr. Stoner to help out at his farm, and be his latest test subject. He's a nice guy, and there really is not much to say about him, as he's pretty bland until he starts growing scales.

Dr. Carl Stoner - The villain of our piece. He's a snake researcher looking for new grant money, and a new test subject. He actually means well enough, and is looking to advance humanity, but in classic horror movie fashion, he plays God and things go too far.

Kristine Stoner - The doctor's daughter, who is also interested in snakes. Especially David's. She's smart, and kind, and again a bit of a blank slate beyond those traits. Loyal to a fault with her father.

Dr. Daniels - A minor character, but Stoner's chief rival, and the man who holds the purse strings. The two doctors have an antagonistic relationship, but there seems to be an undercurrent of past friendship as well, overshadowed by Daniels' position. Or I'm reading too much into things.

For years, I've been utterly fascinated by these separate strands of research that rarely (if ever) intersect. Why is that? Because there's no such thing as “one receptor, one behavior.” And because like most scientific endeavors, neuro-pharmacology/psychiatry research is highly specialized, with experts in one microfield ignoring the literature produced by another (though there are some exceptions).1

Ketamine is a dissociative anesthetic and PCP-derivative that can produce hallucinations and feelings of detachment in non-clinical populations. Phamacologically it's an NMDA receptor antagonist that also acts on other systems (e.g., opioid). Today I'll focus on a recent neuroimaging study that looked at the downsides of ketamine: anhedonia, cognitive disorganization, and perceptual distortions (Pollak et al., 2015).

Imaging Phenomenologically Distinct Effects of Ketamine

In this study, 23 healthy male participants underwent arterial spin labeling (ASL) fMRI scanning while they were infused with either a high dose (0.26 mg/kg bolus + slow infusion) or a low dose (0.13 mg/kg bolus + slow infusion) of ketamine 2 (Pollak et al., 2015). For comparison, the typical dose used in depression studies is 0.5 mg/kg (Wan et al., 2015). Keep in mind that the number of participants in each condition was low, n=12 (after one was dropped) and n=10 respectively, so the results are quite preliminary.

ASL is a post-PET and BOLD-less technique for measuring cerebral blood flow (CBF) without the use of a radioactive tracer (Petcharunpaisan et al., 2010). Instead, water in arterial blood serves as a contrast agent, after being magnetically labeled by applying a 180 degree radiofrequency inversion pulse. Basically, it's a good method for monitoring CBF over a number of minutes.

ASL sequences were obtained before and 10 min after the start of ketamine infusion. Before and after the scan, participants rated their subjective symptoms of delusional thinking, perceptual distortion, cognitive disorganization, anhedonia, mania, and paranoia on the Psychotomimetic States Inventory (PSI). The study was completely open label, so it's not like they didn't know they were getting a mind-altering drug.

Behavioral ratings were quite variable (note the large error bars below), but generally the effects were larger in the high-dose group, as one might expect.

The changes in Perceptual Distortion and Cognitive Disorganization scores were significant for the low-dose group, with the addition of Delusional Thinking, Anhedonia, and Mania in the high-dose group. But again, it's important to remember there was no placebo condition, the significance levels were not all that impressive, and the n's were low.

The CBF results (below) show increases in anterior and subgenual cingulate cortex and decreases in superior and medial temporal cortex, similar to previous studies using PET.

Fig 2a (Pollak et al., 2015). Changes in CBF with ketamine in the low- and high-dose groups overlaid on a high-resolution T1-weighted image.

Did I say the n's were low? The Fig. 2b maps (not shown here) illustrated significant correlations with the Anhedonia and Cognitive Disorganization subscales, but these were based on 10 and 12 data points, when outliers can drive phenomenally large effects. One might like to say...

For [the high-dose] group, ketamine-induced anhedonia inversely related to orbitofrontal cortex CBF changes and cognitive disorganisation was positively correlated with CBF changes in posterior thalamus and the left inferior and middle temporal gyrus. Perceptual distortion was correlated with different regional CBF changes in the low- and high-dose groups.

Nonetheless, the fact remains that ketamine administration in healthy participants caused negative effects like anhedonia and cognitive disorganization at doses lower than those used in studies of treatment-resistant depression (many of which were also open label). Now you can say, “well, controls are not the same as patients with refractory depression” and you'd be right (see Footnote 1). “Glutamatergic signaling profiles” and symptom reports could show a variable relationship, with severe depression at the low end and schizophrenia at the high end (with controls somewhere in the middle).

The antidepressant efficacy of ketamine ... holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

The mysterious and paradoxical ways of ketamine continue...

So take it in don't hold your breath The bottom's all I've found We can't get higher than we get On the Long Way Down

1 One exception is the present study, which discussed the divergent anhedonia results (compared to previous findings of reduced anhedonia in depression). Another example is the work of Dr. John H. Krystal, which includes papers in both the schizophrenia and the treatment-resistant depression realms. However, most of the papers discuss only one and not the other. One notable exception (schizophrenia-related) said this:

...it is important to note that studies examining its effects on glutamateric pathways in the context of mood symptoms (178) may be highly informative for developing our understanding of its relevance to schizophrenia (111). Briefly, emerging models in this area postulate that ketamine may act as anti-depressant by promoting synaptic plasticity via intra-cellular signaling pathways, ultimately promoting brain-derived neurotrophic factor expression via synaptic potentiation (179) and in turns synaptic growth (178). In that sense, acute NMDAR antagonism may promote synaptic plasticity along specific pathways impacted in mood disorders, such as ventral medial PFC (180, 181, p. 916). Conversely, when administered to patients diagnosed with schizophrenia, NMDAR antagonists seem to worsen their symptom profile (182), perhaps by “pushing” an already aberrantly elevated glutamatergic signaling profile upward. Collectively such dissociable effects of ketamine may imply that along distinct circuits there may be an inverted-U relationship between ketamine’s effects and symptoms: depressed patients may be positioned on the low end of the inverted-U (178) and schizophrenia patents may be positioned on the higher end (183). Both task-based and resting-state functional connectivity techniques are well positioned to interrogate such system-level effects of NMDAR antagonists in humans.

2Low-dose ketamine: target plasma level of 50–75 ng/mL was specified (in practice this approximated a rapid bolus of an average of 0.12 mg/kg over 20 s followed by a slow infusion of 0.31 mg/kg/h).

High-dose ketamine: target plasma level of 150 ng/mL was specified (in practice this approximated a rapid bolus of 0.26 mg/kg over 20 s followed by a slow infusion of 0.42 mg/kg/h).

(2) Good reporting / bad reporting.Smith et al. (2015) are to be commended for such an impressive body of work.1 But I still think it was remiss to report a population along a judgmental good/bad binary axis in a cursory manner. The correlation/causation conundrum needs more of a caveat than:

These analyses were driven by and report only correlations; inferring and interpreting the (presumably complex and diverse) causalities remains a challenging issue for the future.

Are some brains wired for a lifestyle that includes education and high levels of satisfaction, while others are wired for anger, rule-breaking, and substance use?

“Wired” implies born that way – no effects of living in poverty in a shitty neighborhood.

Oh, and my flippant observation about the wine cooler/malt liquor axis wasn't actually a major player in the canonical correlation analysis. But race and ethnicity information was indeed collected (but not used: “partly because the race measure is not quantitative, but consists of several distinct categories”).

(3) Ethics! This brings up the larger issue of ethics. A whole host of personal participant information (e.g., genomics from everyone, including hundreds of identical twins) is included in the package. From Van Essen et al. (2013):

The released HCP data are not considered de-identified, insofar as certain combinations of HCP Restricted Data (available through a separate process) might allow identification of individuals as discussed below. It is accordingly important that all investigators who agree to Open Access Data Use Terms consult with their local IRB or Ethics Committee to determine whether the research needs to be approved or declared exempt. If needed and upon request, the HCP will provide a certificate stating that an investigator has accepted the HCP Open Access Data Use Terms. Because HCP participants come from families with twins and non-twin siblings, there is a risk that combinations of information about an individual (e.g., age by year; body weight and height; handedness) might lead to inadvertent identification, particularly by other family members, if these combinations were publicly released.

Oops.

Important Notice to Recipients and System Administrators of HCP Connectome In A Box Hard Drives

Thank you for acquiring a Connectome-in-a-Box that contains HCP image data. This provides an easy and efficient way to transfer large HCP datasets to other labs and institutions wanting to process lots of data, especially when multiple investigators are involved. With it comes a need to insure compliance with HCP’s Data Use Terms as well as any institutional requirements.

And any participant in the study can look at the results and infer, because of their regular cannabis use and their father's history of heavy drinking, that they must have a “bad brain.” Do the investigators have an obligation to counsel them on what this might mean (and what they should do)? Yeah, stop smoking cigarettes and pot, but there's not much they can do about their father's substance abuse or their fluid intelligence.

(4) Biology. Finally, I'm not sure what the finding means biologically. Across a population, there's a general mode of functional connectivity while participants lie in a scanner with nothing to do. That falls along an axis of “positive” and “negative” traits. And this pattern of correlated hemodynamic activity across 30 node-pair edges means....... what, exactly?

Every person's connectome is unique (“I am my connectome” for the thousandth time).2 But this mantra more commonly refers to the fine-grained structural connectome. You know, the kind that will live forever and be uploaded to a computer (see Amy Harmon's article on The Neuroscience of Immortality, which caused quite a splash).

What is the relationship between resting state functional connectivity and the implementation of thought and behavior via neural codes? This must be exceptionally unique for each person. We know this because even in lowly organisms like flies, neurons in an olfactory region called the mushroom bodies show a striking degree of individuality in neural codingacross animals.3

At the single-cell level, we show that uniquely identifiable MBONs [mushroom body output neurons, n=34] displayprofoundly different tuning across different animals, but that tuning of the same neuron across the two hemispheres of an individual fly was nearly identical.

In other words, a fly's unique olfactory experience shapes the response properties of a tiny set of neurons, even for animals reared under the same conditions. “In several cases, we even recorded on the same day from progeny of the same cross, raised in the same food vial” (Hige et al., 2015).

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.